Heavy metals such as Zn2+, Fe2+, Cu2+, Cr(VI), Se2+, Mn2+, Mo2+, etc. at low concentrations are essential micronutrients for living organisms. However, they can exert toxic effect at high concentrations. Contamination of the environment with continuous release of toxic heavy metals has been documented in numerous surveys and has become a major public health concern. Evidence from largely in vitro studies is mounting that interactions of Cd(II) and Cr(VI) with DNA, proteins and some enzymes may be involved in the still ill-understood pathogenesis of heavy metal-related mutagenesis and carcinogenesis. Metallothioneins formed in response to exposure of animals to heavy metals, (e.g., Cd2+, Zn2+, Cr6+, Cu2+, Hg2+) are involved in the formation of reactive radicals that may represent the initial step in the mechanisms of heavy metal toxicity. In addition, the literature is replete with instances of heavy metal inactivation of critical metabolic enzymes, Mg(II)-ATPases of membranes, glutathione reductase of red blood cells, electron transport enzymes of mitochondria, etc. The current proposal focuses on the molecular mechanisms of in vivo interactions of Cd(II) and/or Cr(VI) with cellular biomolecules with the following specific objectives: 1) to examine DNA strand breaks in mammalian cells exposed to Cd and/or Cr(VI), 2) to investigate the genotoxic effects of heavy metals on the fidelity of DNA polymerases, 3) to determine the effects of heavy metals on the kinetics of some critical metabolic enzymes, 4) to develop reliable and sensitive biochemical indices of exposure to heavy metals, and 5) to provide a strong biotechnology and molecular toxicology research experience to the group of minority students that will be participating in this project.